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Article ; Online: UGT1A1

Mathew, Jenny Mary / Mpangase, Phelelani Thokozani / Sengupta, Dhriti / Kwenda, Stanford / Mavri-Damelin, Demetra / Ramsay, Michèle

Pharmacogenomics

2021 Volume 22, Issue 15, Page(s) 963–972

Abstract: Aim: ...

Abstract	Aim:
MeSH term(s)	Anti-HIV Agents/pharmacokinetics ; Anti-HIV Agents/therapeutic use ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/therapeutic use ; Antineoplastic Agents, Phytogenic ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/genetics ; Computational Biology ; Genotype ; Glucuronosyltransferase/genetics ; HIV Infections/drug therapy ; HIV Infections/genetics ; Heterocyclic Compounds, 3-Ring/pharmacokinetics ; Heterocyclic Compounds, 3-Ring/therapeutic use ; Humans ; Irinotecan/pharmacokinetics ; Irinotecan/therapeutic use ; Liver/enzymology ; Oxazines/pharmacokinetics ; Oxazines/therapeutic use ; Piperazines/pharmacokinetics ; Piperazines/therapeutic use ; Pyridones/pharmacokinetics ; Pyridones/therapeutic use ; Quality Control ; South Africa ; Treatment Outcome ; Up-Regulation
Chemical Substances	Anti-HIV Agents ; Antineoplastic Agents ; Antineoplastic Agents, Phytogenic ; Heterocyclic Compounds, 3-Ring ; Oxazines ; Piperazines ; Pyridones ; Irinotecan (7673326042) ; dolutegravir (DKO1W9H7M1) ; UGT1A1 enzyme (EC 2.4.1.-) ; Glucuronosyltransferase (EC 2.4.1.17)
Language	English
Publishing date	2021-09-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2019513-8
ISSN	1744-8042 ; 1462-2416
ISSN (online)	1744-8042
ISSN	1462-2416
DOI	10.2217/pgs-2021-0062
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Article ; Online: Development of a Novel DNA Mono-alkylator Platform for Antibody-Drug Conjugates.

Molecular cancer therapeutics

2024 Volume 23, Issue 4, Page(s) 541–551

Abstract: Although microtubule inhibitors (MTI) remain a therapeutically valuable payload option for antibody-drug conjugates (ADC), some cancers do not respond to MTI-based ADCs. Efforts to fill this therapeutic gap have led to a recent expansion of the ADC ... ...

Abstract	Although microtubule inhibitors (MTI) remain a therapeutically valuable payload option for antibody-drug conjugates (ADC), some cancers do not respond to MTI-based ADCs. Efforts to fill this therapeutic gap have led to a recent expansion of the ADC payload "toolbox" to include payloads with novel mechanisms of action such as topoisomerase inhibition and DNA cross-linking. We present here the development of a novel DNA mono-alkylator ADC platform that exhibits sustained tumor growth suppression at single doses in MTI-resistant tumors and is well tolerated in the rat upon repeat dosing. A phosphoramidate prodrug of the payload enables low ADC aggregation even at drug-to-antibody ratios of 5:1 while still delivering a bystander-capable payload that is effective in multidrug resistant (MDR)-overexpressing cell lines. The platform was comparable in xenograft studies to the clinical benchmark DNA mono-alkylator ADC platform DGN459 but with a significantly better tolerability profile in rats. Thus, the activity and tolerability profile of this new platform make it a viable option for the development of ADCs.
MeSH term(s)	Humans ; Rats ; Animals ; Immunoconjugates/pharmacology ; Immunoconjugates/therapeutic use ; Alkylating Agents ; Neoplasms/drug therapy ; DNA/metabolism ; Cell Line, Tumor ; Antineoplastic Agents/pharmacology
Chemical Substances	Immunoconjugates ; Alkylating Agents ; DNA (9007-49-2) ; Antineoplastic Agents
Language	English
Publishing date	2024-02-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-23-0622
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Book ; Online: On Min-Max affine approximants of convex or concave real valued functions from $\mathbb R^k$, Chebyshev equioscillation and graphics

Damelin, Steven B. / Ragozin, David L. / Werman, Michael

2018

Abstract: We study Min-Max affine approximants of a continuous convex or concave function $f:\Delta\subset \mathbb R^k\xrightarrow{} \mathbb R$ where $\Delta$ is a convex compact subset of $\mathbb R^k$. In the case when $\Delta$ is a simplex we prove that there ... ...

Abstract	We study Min-Max affine approximants of a continuous convex or concave function $f:\Delta\subset \mathbb R^k\xrightarrow{} \mathbb R$ where $\Delta$ is a convex compact subset of $\mathbb R^k$. In the case when $\Delta$ is a simplex we prove that there is a vertical translate of the supporting hyperplane in $\mathbb R^{k+1}$ of the graph of $f$ at the vertices which is the unique best affine approximant to $f$ on $\Delta$. For $k=1$, this result provides an extension of the Chebyshev equioscillation theorem for linear approximants. Our result has interesting connections to the computer graphics problem of rapid rendering of projective transformations.
Keywords	Mathematics - Optimization and Control ; Computer Science - Computer Vision and Pattern Recognition ; Mathematics - Classical Analysis and ODEs ; 49J30 ; 49J35 ; 49J10 ; 49J21 (Primary) ; 94A08 (Secondary)
Publishing date	2018-12-05
Publishing country	us
Document type	Book ; Online
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Article ; Online: Evolving Strategies for Target Selection for Antibody-Drug Conjugates.

Damelin, Marc / Zhong, Wenyan / Myers, Jeremy / Sapra, Puja

Pharmaceutical research

2015 Volume 32, Issue 11, Page(s) 3494–3507

Abstract: Antibody-drug conjugates (ADCs) represent a promising modality for the treatment of cancer. The therapeutic strategy is to deliver a potent drug preferentially to the tumor and not normal tissues by attaching the drug to an antibody that recognizes a ... ...

Abstract	Antibody-drug conjugates (ADCs) represent a promising modality for the treatment of cancer. The therapeutic strategy is to deliver a potent drug preferentially to the tumor and not normal tissues by attaching the drug to an antibody that recognizes a tumor antigen. The selection of antigen targets is critical to enabling a therapeutic window for the ADC and has proven to be surprisingly complex. We surveyed the tumor and normal tissue expression profiles of the targets of ADCs currently in clinical development. Our analysis demonstrates a surprisingly broad range of expression profiles and the inability to formalize any optimal parameters for an ADC target. In this context, we discuss additional considerations for ADC target selection, including interdependencies among biophysical properties of the drug, biological functions of the target and strategies for clinical development. The TPBG (5T4) oncofetal antigen and the anti-TPBG ADC A1-mcMMAF are highlighted to demonstrate the relevance of the target's biological function. Emerging platform technologies and novel biological insights are expanding ADC target space and transforming strategies for target selection.
MeSH term(s)	Antibodies, Monoclonal/chemistry ; Antibodies, Monoclonal/pharmacology ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Databases, Genetic ; Drug Design ; Humans ; Immunoconjugates/chemistry ; Immunoconjugates/pharmacology ; Membrane Proteins/genetics ; Molecular Targeted Therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; Proteome/genetics ; Transcriptome
Chemical Substances	Antibodies, Monoclonal ; Antineoplastic Agents ; Immunoconjugates ; Membrane Proteins ; Proteome
Language	English
Publishing date	2015-01-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	843063-9
ISSN	1573-904X ; 0724-8741 ; 0739-0742
ISSN (online)	1573-904X
ISSN	0724-8741 ; 0739-0742
DOI	10.1007/s11095-015-1624-3
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Article ; Online: Site-Specific Dolasynthen Antibody-Drug Conjugates Exhibit Consistent Pharmacokinetic Profiles across a Wide Range of Drug-to-Antibody Ratios.

Clardy, Susan M / Uttard, Alex / Du, Bingfan / Catcott, Kalli C / Lancaster, Kelly L / Ditty, Elizabeth / Sadowsky, Jack / Zurita, Jeffrey / Malli, Naniye / Qin, LiuLiang / Bradley, Stephen P / Avocetien, Kenneth / Carter, Tyler / Kim, Dokyong / Nazzaro, Mark / Xu, Ling / Pillow, Thomas H / Zacharias, Neelie T / Lewis, Gail D /

Rowntree, Rebecca K / Iyengar, Radha / Lee, David H / Damelin, Marc / Toader, Dorin / Lowinger, Timothy B

Molecular cancer therapeutics

2023 Volume 23, Issue 1, Page(s) 84–91

Abstract: Key defining attributes of an antibody-drug conjugate (ADC) include the choice of the targeting antibody, linker, payload, and the drug-to-antibody ratio (DAR). Historically, most ADC platforms have used the same DAR for all targets, regardless of target ...

Abstract	Key defining attributes of an antibody-drug conjugate (ADC) include the choice of the targeting antibody, linker, payload, and the drug-to-antibody ratio (DAR). Historically, most ADC platforms have used the same DAR for all targets, regardless of target characteristics. However, recent studies and modeling suggest that the optimal DAR can depend on target expression level and intratumoral heterogeneity, target internalization and trafficking, and characteristics of the linker and payload. An ADC platform that enables DAR optimization could improve the success rate of clinical candidates. Here we report a systematic exploration of DAR across a wide range, by combining THIOMAB protein engineering technology with Dolasynthen, an auristatin-based platform with monomeric and trimeric variants. This approach enabled the generation of homogeneous, site-specific ADCs spanning a discrete range of DARs 2, 4, 6, 12, and 18 by conjugation of trastuzumab IgG1 THIOMAB constructs with 1, 2, or 3 engineered cysteines to monomeric or trimeric Dolasynthen. All ADCs had physicochemical properties that translated to excellent in vivo pharmacology. Following a single dose of ADCs in a HER2 xenograft model with moderate antigen expression, our data demonstrated comparable pharmacokinetics for the conjugates across all DARs and dose-dependent efficacy of all test articles. These results demonstrate that the Dolasynthen platform enables the generation of ADCs with a broad range of DAR values and with comparable physiochemical, pharmacologic, and pharmacokinetics profiles; thus, the Dolasynthen platform enables the empirical determination of the optimal DAR for a clinical candidate for a given target.
MeSH term(s)	Humans ; Immunoconjugates/chemistry ; Xenograft Model Antitumor Assays ; Trastuzumab/pharmacology ; Trastuzumab/chemistry ; Receptor, ErbB-2/metabolism ; Cysteine
Chemical Substances	Immunoconjugates ; Trastuzumab (P188ANX8CK) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Cysteine (K848JZ4886)
Language	English
Publishing date	2023-09-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-23-0262
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Article ; Online: Discovery and Optimization of a STING Agonist Platform for Application in Antibody Drug Conjugates.

Duvall, Jeremy R / Thomas, Joshua D / Bukhalid, Raghida A / Catcott, Kalli C / Bentley, Keith W / Collins, Scott D / Eitas, Timothy / Jones, Brian D / Kelleher, Eugene W / Lancaster, Kelly / Protopopova, Marina / Ray, Soumya S / Ter-Ovanesyan, Elena / Xu, Ling / Yang, Liping / Zurita, Jeffrey / Damelin, Marc / Toader, Dorin / Lowinger, Timothy B

Journal of medicinal chemistry

2023 Volume 66, Issue 15, Page(s) 10715–10733

Abstract: While STING agonists have proven to be effective preclinically as anti-tumor agents, these promising results have yet to be translated in the clinic. A STING agonist antibody-drug conjugate (ADC) could overcome current limitations by improving tumor ... ...

Abstract	While STING agonists have proven to be effective preclinically as anti-tumor agents, these promising results have yet to be translated in the clinic. A STING agonist antibody-drug conjugate (ADC) could overcome current limitations by improving tumor accessibility, allowing for systemic administration as well as tumor-localized activation of STING for greater anti-tumor activity and better tolerability. In line with this effort, a STING agonist ADC platform was identified through systematic optimization of the payload, linker, and scaffold based on multiple factors including potency and specificity in both in vitro and in vivo evaluations. The platform employs a potent non-cyclic dinucleotide STING agonist, a cleavable ester-based linker, and a hydrophilic PEG8-bisglucamine scaffold. A tumor-targeted ADC built with the resulting STING agonist platform induced robust and durable anti-tumor activity and demonstrated high stability and favorable pharmacokinetics in nonclinical species.
MeSH term(s)	Humans ; Immunoconjugates/pharmacokinetics ; Antibodies, Monoclonal ; Antineoplastic Agents/pharmacokinetics ; Neoplasms/drug therapy
Chemical Substances	Immunoconjugates ; Antibodies, Monoclonal ; Antineoplastic Agents
Language	English
Publishing date	2023-07-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.3c00907
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Article ; Online: Disulfiram/copper-disulfiram Damages Multiple Protein Degradation and Turnover Pathways and Cytotoxicity is Enhanced by Metformin in Oesophageal Squamous Cell Carcinoma Cell Lines.

Jivan, Rupal / Damelin, Leonard Howard / Birkhead, Monica / Rousseau, Amanda Louise / Veale, Robin Bruce / Mavri-Damelin, Demetra

Journal of cellular biochemistry

2015 Volume 116, Issue 10, Page(s) 2334–2343

Abstract: Disulfiram (DSF), used since the 1950s in the treatment of alcoholism, is reductively activated to diethyldithiocarbamate and both compounds are thiol-reactive and readily complex copper. More recently DSF and copper-DSF (Cu-DSF) have been found to ... ...

Abstract	Disulfiram (DSF), used since the 1950s in the treatment of alcoholism, is reductively activated to diethyldithiocarbamate and both compounds are thiol-reactive and readily complex copper. More recently DSF and copper-DSF (Cu-DSF) have been found to exhibit potent anticancer activity. We have previously shown that the anti-diabetic drug metformin is anti-proliferative and induces an intracellular reducing environment in oesophageal squamous cell carcinoma (OSCC) cell lines. Based on these observations, we investigated the effects of Cu-DSF and DSF, with and without metformin, in this present study. We found that Cu-DSF and DSF caused considerable cytotoxicity across a panel of OSCC cells, and metformin significantly enhanced the effects of DSF. Elevated copper transport contributes to DSF and metformin-DSF-induced cytotoxicity since the cell-impermeable copper chelator, bathocuproinedisulfonic acid, partially reversed the cytotoxic effects of these drugs, and interestingly, metformin-treated OSCC cells contained higher intracellular copper levels. Furthermore, DSF may target cancer cells preferentially due to their high dependence on protein degradation/turnover pathways, and we found that metformin further enhances the role of DSF as a proteasome inhibitor. We hypothesized that the lysosome could be an additional, novel, target of DSF. Indeed, this acid-labile compound decreased lysosomal acidification, and DSF-metformin co-treatment interfered with the progression of autophagy in these cells. In summary, this is the first such report identifying the lysosome as a target of DSF and based on the considerable cytotoxic effects of DSF either alone or in the presence of metformin, in vitro, and we propose these as novel potential chemotherapeutic approaches for OSCC.
MeSH term(s)	Carcinoma, Squamous Cell/drug therapy ; Carcinoma, Squamous Cell/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Copper/administration & dosage ; Disulfiram/administration & dosage ; Drug Synergism ; Esophageal Neoplasms/drug therapy ; Esophageal Neoplasms/pathology ; Esophageal Squamous Cell Carcinoma ; Humans ; Metformin/administration & dosage ; Proteasome Endopeptidase Complex/administration & dosage ; Proteolysis/drug effects
Chemical Substances	Copper (789U1901C5) ; Metformin (9100L32L2N) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Disulfiram (TR3MLJ1UAI)
Language	English
Publishing date	2015-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	392402-6
ISSN	1097-4644 ; 0730-2312
ISSN (online)	1097-4644
ISSN	0730-2312
DOI	10.1002/jcb.25184
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Article: Diversity of arbuscular mycorrhizal (AM) fungi colonising roots of indigenous Vachellia and Senegalia trees on gold and uranium mine tailings in South Africa

Buck, M.T / C.J. Straker / D. Mavri-Damelin / I.M. Weiersbye

SAAB South African journal of botany. 2019 Mar., v. 121

2019

Abstract: The gold and uranium mines of the Free State gold fields in South Africa are no longer mined underground but provide a rich source of biological data for analysis from the different rehabilitation programmes designed to revegetate the above-ground ... ...

Abstract	The gold and uranium mines of the Free State gold fields in South Africa are no longer mined underground but provide a rich source of biological data for analysis from the different rehabilitation programmes designed to revegetate the above-ground tailings. Some of the programmes have incorporated the application of mycorrhizal fungal inoculum and the aim of this study was to assess the arbuscular mycorrhiza (AM) fungal diversity in the roots of trees being used for two different phytoremediation trials. The trees sampled were indigenous acacias (Vachellia and Senegalia spp.) and two tailings assessed were (i), planted with trees which had been inoculated with crude AM fungal inocula in the nursery and received no organic inputs and (ii), ameliorated with garden refuse, on which the acacias were natural colonisers. The approach was to target and amplify the small subunit rRNA gene sequences, a marker gene widely used in ecological studies for phylogenetic analysis to determine AM fungal diversity. This study identified 17 different AM fungal species that fell within 8 genera, namely, Diversispora, Rhizophagus, Scutellospora, Claroideoglomus, Cetraspora, Sclerocystis, Glomus and Redecker. From the planted mine tailing 8 genera and 13 species were identified of which 5 species were unique to the tailing, and from the garden refuse-ameliorated mine tailing 6 genera and 12 species were identified of which 4 species were unique to the tailing. A limited soil physico-chemical analysis of the substrata revealed no significant difference between the sites except for the element Al, whose concentration on site (i) was almost double that of site (ii). The elements Pb, Hg, Mo, Ni, Pt and Th were not detected. The results represent the first AM fungal diversity study from South Africa sampling root DNA and report 9 first records of AM fungal species in South Africa. A high number of AM fungal taxa were identified when compared with other diversity studies on metal-contaminated sites, all of which exhibited substantially higher levels of pollutant elements than the Free State sites.
Keywords	Acacia ; Claroideoglomus ; DNA ; Diversispora ; Glomus ; Scutellospora ; Senegalia ; Vachellia ; aluminum ; garden residues ; gardens ; genetic markers ; gold ; inoculum ; lead ; mercury ; mine tailings ; mycorrhizal fungi ; nickel ; nucleotide sequences ; phylogeny ; phytoremediation ; platinum ; pollutants ; ribosomal RNA ; roots ; soil ; trees ; uranium ; vesicular arbuscular mycorrhizae ; South Africa
Language	English
Dates of publication	2019-03
Size	p. 34-44.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	2126918-X
ISSN	0254-6299
ISSN	0254-6299
DOI	10.1016/j.sajb.2018.10.014
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Article ; Online: Identification and sequence analysis of two novel cryptic plasmids isolated from the vaginal mucosa of South African women.

Harris, Lyle / van Zyl, Leonardo J / Kirby-McCullough, Bronwyn M / Damelin, Leonard H / Tiemessen, Caroline T / Trindade, Marla

Plasmid

2018 Volume 98, Page(s) 56–62

Abstract: The vaginal mucosa is dominated by Gram positive, rod shaped lactobacilli which serve as a natural barrier against infection. In both healthy- and bacterial vaginosis (BV)-infected women Lactobacillus crispatus and Lactobacillus jensenii have been found ... ...

Abstract	The vaginal mucosa is dominated by Gram positive, rod shaped lactobacilli which serve as a natural barrier against infection. In both healthy- and bacterial vaginosis (BV)-infected women Lactobacillus crispatus and Lactobacillus jensenii have been found to be the predominant Lactobacillus species. Many studies have been conducted to assess factors influencing lactobacilli dominance in the vaginal microbiome. In the present study two plasmids, pLc4 and pLc17, isolated from vaginal Lactobacillus strains of both healthy and BV-infected women were characterized. The smaller plasmid, pLc4 (4224 bp), was detected in both L. crispatus and L. jensenii strains, while pLc17 was only detected in L. crispatus. Based on its nucleotide sequence pLc4 appears highly novel, with its replication protein having 44% identity to the replication initiation protein of pSMQ173b_03. Phylogenetic analysis with other Rolling Circle Replication plasmids confirmed that pLc4 shows a low degree of similarity to these plasmids. Plasmid pLc17 (16,663 bp) appears to carry both a RCR replicon and a theta replicon, which is rare in naturally occurring plasmids. pLc4 was maintained at a high copy number of 29, while pLc17 appears to be a medium copy number plasmid maintained at 11 copies per chromosome. While sequence analysis is a valuable tool to study cryptic plasmids, further function-based analysis will be required in order to fully elucidate the role of these plasmids within the vaginal milieu.
MeSH term(s)	DNA, Bacterial/genetics ; Female ; Humans ; Lactobacillus/classification ; Lactobacillus/genetics ; Lactobacillus/isolation & purification ; Lactobacillus/metabolism ; Microbiota ; Mucous Membrane/microbiology ; Phylogeny ; Plasmids/chemistry ; Plasmids/genetics ; Sequence Analysis, DNA ; South Africa/epidemiology ; Vagina/microbiology ; Vaginosis, Bacterial/epidemiology ; Vaginosis, Bacterial/microbiology
Chemical Substances	DNA, Bacterial
Language	English
Publishing date	2018-09-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	282384-6
ISSN	1095-9890 ; 0147-619X
ISSN (online)	1095-9890
ISSN	0147-619X
DOI	10.1016/j.plasmid.2018.09.008
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Article: The decatenation checkpoint.

Damelin, M / Bestor, T H

British journal of cancer

2007 Volume 96, Issue 2, Page(s) 201–205

Abstract: The decatenation checkpoint delays entry into mitosis until the chromosomes have been disentangled. Deficiency in or bypass of the decatenation checkpoint can cause chromosome breakage and nondisjunction during mitosis, which results in aneuploidy and ... ...

Abstract	The decatenation checkpoint delays entry into mitosis until the chromosomes have been disentangled. Deficiency in or bypass of the decatenation checkpoint can cause chromosome breakage and nondisjunction during mitosis, which results in aneuploidy and chromosome rearrangements in the daughter cells. A deficiency in the decatenation checkpoint has been reported in lung and bladder cancer cell lines and may contribute to the accumulation of chromosome aberrations that commonly occur during tumour progression. A checkpoint deficiency has also been documented in cultured stem and progenitor cells, and cancer stem cells are likely to be derived from stem and progenitor cells that lack an effective decatenation checkpoint. An inefficient decatenation checkpoint is likely to be a source of the chromosome aberrations that are common features of most tumours, but an inefficient decatenation checkpoint in cancer stem cells could also provide a potential target for chemotherapy.
MeSH term(s)	Cell Line, Tumor ; Chromosomal Instability ; G2 Phase ; Humans ; Loss of Heterozygosity ; Neoplasms/genetics ; Neoplasms/pathology ; Stem Cells/cytology
Language	English
Publishing date	2007-01-29
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/sj.bjc.6603537
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